Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials.

BACKGROUND: Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown preliminary efficacy in people with relapsing multiple sclerosis in a phase 2 trial. Here, we aimed to compare the safety and efficacy of evobrutinib with the active comparator teriflunomide in people with relapsing multiple sclerosis. METHODS: EvolutionRMS1 and evolutionRMS2 were two multicentre, randomised, double-blind, double-dummy, active-controlled, phase 3 trials conducted at 701 multiple sclerosis centres and neurology clinics in 52 countries. Adults aged 18-55 years with relapsing multiple sclerosis (Expanded Disability Status Scale [EDSS] score of 0·0-5·5) were included. Participants were randomly assigned (1:1) using a central interactive web response system to receive either evobrutinib (45 mg twice per day with placebo once per day) or teriflunomide (14 mg once per day with placebo twice per day), all taken orally and in an unfasted state, with randomisation stratified by geographical region and baseline EDSS. All study staff and participants were masked to the study interventions. The primary endpoint for each study was annualised relapse rate based on adjudicated qualified relapses up to 156 weeks, assessed in the full analysis set (defined as all randomly assigned participants) with a negative binomial model. These studies are registered with ClinicalTrials.gov (NCT04338022 for evolutionRMS1 and NCT04338061 for evolutionRMS2, both are terminated). FINDINGS: The primary analysis was done using data for 2290 randomly assigned participants collected from June 12, 2020, to Oct 2, 2023. 1124 participants were included in the full analysis set in evolutionRMS1 (560 in the evobrutinib group and 564 in the teriflunomide group) and 1166 in evolutionRMS2 (583 in each group). 751 (66·8%) participants were female and 373 (33·1%) were male in evolutionRMS1, whereas 783 (67·2%) were female and 383 (32·8%) were male in evolutionRMS2. Annualised relapse rate was 0·15 (95% CI 0·12-0·18 with evobrutinib vs 0·14 [0·11-0·18] with teriflunomide (adjusted RR 1·02 [0·75-1·39]; p=0·55) in evolutionRMS1 and 0·11 (0·09-0·13 vs 0·11 [0·09-0·13]; adjusted RR 1·00 [0·74-1·35]; p=0·51) in evolutionRMS2. The pooled proportion of participants with any treatment-emergent adverse event (TEAE) was similar between treatment groups (976 [85·6%] of 1140 with evobrutinib vs 999 [87·2%] of 1146 with teriflunomide). The most frequently reported TEAEs were COVID-19 (223 [19·6%] with evobrutinib vs 223 [19·5%] with teriflunomide), alanine aminotransferase increased (173 [15·2%] vs 204 [17·8%]), aspartate aminotransferase increased (110 [9·6%] vs 131 [11·4%]), and headache (175 [15·4%] vs 176 [15·4%]). Serious TEAE incidence rates were higher with evobrutinib than teriflunomide (86 [7·5%] vs 64 [5·6%]). Liver enzyme elevations at least 5 × upper limit of normal were more common with evobrutinib than with teriflunomide, particularly in the first 12 weeks (55 [5·0%] vs nine [<1%]). Three people who received evobrutinib and one who received teriflunomide met the biochemical definition of Hy's law; all cases resolved after discontinuation of treatment. There were two deaths (one in each group), neither related to study treatment. INTERPRETATION: The efficacy of evobrutinib was not superior to that of teriflunomide. Together, efficacy and liver-related safety findings do not support the use of evobrutinib in people with relapsing multiple sclerosis. FUNDING: Merck.

Increased periventricular thalamic damage gradient in multiple sclerosis detected by quantitative gradient echo MRI.

OBJECTIVE: Thalamic tissue damage in multiple sclerosis (MS) follows a 'surface-in' gradient from the ventricular surface. The clinical consequences of this gradient are not completely understood. Using quantitative gradient-recalled echo (qGRE) MRI, we evaluated a periventricular thalamic gradient of tissue integrity in MS and its relationship with clinical variables. METHODS: Structural and qGRE MRI scans were acquired for a cohort of MS patients and healthy controls (HC). qGRE-derived R2t* values were used as a measure of tissue integrity. Thalamic segmentations were divided into 1-mm concentric bands radiating from the ventricular surface, excluding the CSF-adjacent band. Median R2t* values within these bands were used to calculate the periventricular thalamic gradient. RESULTS: We included 44 MS patients and 17 HC. R2t* increased slightly with distance from the ventricular surface in HC. MS patients had a steeper periventricular thalamic gradient compared to HC (mean slope 0.55 vs. 0.36; p < 0.001), which correlated with longer disease duration (ß = 0.001 /year; p = 0.027) and higher Expanded Disability Status Scale (EDSS) score (ß = 0.07 /EDSS point; p = 0.019). Left and right thalamus were symmetrically affected. CONCLUSIONS: We detected an increased thalamic gradient in MS in vivo using qGRE MRI, which correlated with disease duration and greater clinical disability. These findings further support the 'surface-in' pathology hypothesis in MS and suggest a CSF-mediated process given symmetric bi-thalamic involvement.

MS treatment de-escalation: review and commentary.

Almost all currently licensed disease-modifying therapies (DMTs) for MS treatment require prolonged if not lifelong administration. Yet, as people age, the immune system has increasingly reduced responsiveness, known as immunosenescence. Many MS DMTs reduce the responsiveness of the immune system, increasing the risks for infections and possibly cancers. As people with MS (pwMS) age, it is recognized that inflammatory MS activity declines. Several studies have addressed de-escalation of DMTs for relapsing MS under special circumstances. Here, we review evidence for de-escalating DMTs as a strategy that is particularly relevant to pwMS of older age. Treatment de-escalation can involve various strategies, such as extended or reduced dosing, switching from high-efficacy DMTs having higher risks to moderately effective DMTs with lesser risks, or treatment discontinuation. Studies have suggested that for natalizumab extended dosing maintained clinical efficacy while reducing the risk of PML. Extended interval dosing of ocrelizumab mitigated the decline of Ig levels. Retrospective and observational discontinuation studies demonstrate that age is an essential modifier of drug efficacy. Discontinuation of MS treatment in older patients has been associated with a stable disease course, while younger patients who discontinued treatment were more likely to experience new clinical activity. A recently completed 2-year randomized-controlled discontinuation study in 260 stable pwMS > 55 years found stable clinical multiple sclerosis with only a small increased risk of new MRI activity upon discontinuation. DMT de-escalation or discontinuation in MS patients older than 55 years may be non-inferior to continued treatment with immunosuppressive agents having higher health risks. However, despite several small studies, a definite conclusion about treatment de-escalation in older pwMS will require larger and longer studies. Ideally, comparison of de-escalation versus continuation versus discontinuation of DMTs should be done by prospective randomized-controlled trials enrolling sufficient numbers of subjects to allow comparisons for MS patients of both sexes within age groups, such as 55-59, 60-65, 66-69, etc. Optimally, such studies should be 3 years or longer and should incorporate testing for specific markers of immunosenescence (such as T-cell receptor excision circles) to account for differential aging of individuals.

Randomised controlled trial of intermittent calorie restriction in people with multiple sclerosis.

BACKGROUND: Calorie restriction (CR) ameliorates preclinical models of multiple sclerosis (MS) via multiple mechanisms. These include decreased leptin, a proinflammatory adipokine, but mechanistic studies in humans are lacking. Tests of daily and intermittent CR (iCR) in people with MS (pwMS) showed improvements in fatigue and well-being measures. This trial studied the effects of 12-week iCR on metabolic, immunological, and clinical outcomes in pwMS. METHOD: Relapsing-remitting MS participants were randomised to iCR or a control group. Study visits were conducted at baseline, 6 and 12 weeks. The primary outcome was reduction in serum leptin levels at 12 weeks. Feasibility and safety were assessed by diet adherence and adverse events (AEs). Secondary outcomes included changes in anthropometric and body composition measures, metabolic and immunologic profiling, and clinical measures. Mixed effects linear regression models were used to evaluate outcome differences between and within groups over time. RESULTS: Forty-two pwMS were randomised, 34 completed the study (17/group). Leptin serum levels at 12 weeks were significantly lower in the iCR versus the control group (mean decrease -6.98 µg/dL, 95% CI: -28.02 to 14.06; p=0.03). Adherence to iCR was 99.5% and 97.2% at 6 and 12 weeks, respectively, and no serious AEs were reported. An increase in blood CD45RO+ regulatory T-cell numbers was seen after 6 weeks of iCR. Exploratory cognitive testing demonstrated a significant improvement in the Symbol Digit Modality Test Score in the iCR group at 12 weeks. CONCLUSIONS: iCR has the potential to benefit metabolic and immunologic profiles and is safe and feasible in pwMS. TRIAL REGISTRATION NUMBER: NCT03539094 .

Unexpected Low Rate of Amyloid-ß Pathology in Multiple Sclerosis Patients.

The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid-ß plasma biomarker positivity was approximately half the rate in 300 non-MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid-ß pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024;96:453-459.

Functional outcomes of diets in multiple sclerosis (FOOD for MS): Protocol for a parallel arm randomized feeding trial for low glycemic load and calorie restriction.

BACKGROUND: Pilot trials indicate that both a low glycemic load (GL) diet and calorie restriction (CR) can be implemented successfully in people with multiple sclerosis (pMS) and may improve MS symptoms and physical function, but large randomized clinical trials (RCTs) have not yet been conducted. The purpose of this study is to test these interventions alone and in combination to determine their efficacy for improving clinical and patient reported outcomes (PROs) in pMS. METHODS: This 32-week, two-arm, RCT at two centers will randomly assign 100 adults with relapsing-remitting or secondary progressive MS to a low GL diet (n = 50) or a standard GL diet (n = 50). Both diet groups will complete two study phases: a eucaloric phase (16 weeks) and a CR phase (16 weeks). Groceries for the study meal plans will be delivered to participants' homes weekly. The primary outcome is physical function, measured by timed 25-ft walk test. Secondary outcomes are pain, fatigue, mood, and anxiety. DISCUSSION: This will be the most rigorous intervention trial to date of a low GL diet and CR in adults with MS, and among the first to assess the impact of intentional weight loss on MS symptoms. Results will provide valuable insight for recommending dietary change, weight loss, or both to adults with MS. These non-drug interventions pose few risks and have potential to yield significant improvements in MS symptoms. TRIAL REGISTRATION ID: NCT05327322.

Prevalence of anti-myelin oligodendrocyte glycoprotein antibodies across neuroinflammatory and neurodegenerative diseases.

Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in patients with CNS diseases, including MS and ALS. In total, 771 serum samples from the John L. Trotter MS Center and the Northeast ALS Consortium were examined using a live cell-based assay for detection of anti-MOG IgG1. Samples from three cohorts were tested in blinded fashion: healthy control (HC) subjects, patients with clinically diagnosed MOGAD, and an experimental group of ALS and MS patients. All samples from established MOGAD cases were positive for anti-MOG antibodies, while all HC samples were negative. Anti-MOG IgG1 was detected in 65 of 658 samples (9.9%) from MS subjects and 4 of 108 (3.7%) samples from ALS subjects. The presence of serum anti-MOG IgG1 in MS and ALS patients raises questions about the contribution of these antibodies to disease pathophysiology as well as accuracy of diagnostic approaches for CNS inflammatory diseases.

Exploring the association between weight loss-inducing medications and multiple sclerosis: insights from the FDA adverse event reporting system database.

Background: Several studies have demonstrated that early childhood and adolescent obesity are risk factors for multiple sclerosis (MS) susceptibility. Obesity is thought to share inflammatory components with MS through overproduction of pro-inflammatory adipokines (e.g., leptin) and reduction of anti-inflammatory adipokines (e.g, adiponectin). Recently, drug repurposing (i.e. identifying new indications for existing drugs) has garnered significant attention. The US Food and Drug Administration Adverse Event Reporting System (FAERS) database serves not only as a resource for mining adverse drug reactions and safety signals but also for identifying inverse associations and potential medication repurposing opportunities. Objective: We aimed to explore the association between weight-loss-inducing drugs and MS using real-world reports from the FAERS database. Design: Secondary analysis of existing data from the FAERS database. Methods: We conducted a disproportionality analysis using the FAERS database between the fourth quarter of 2003 and the second quarter of 2023 to explore associations between MS and weight loss-inducing drugs. Disproportionality was quantified using the reporting odds ratio (ROR). An inverse association was defined when the upper limit of the 95% confidence interval for ROR was <1. Results: We found an inverse association between MS and anti-diabetic weight loss-inducing drugs including semaglutide (ROR: 0.238; 95% CI: 0.132-0.429), dulaglutide (ROR: 0.165; 95% CI: 0.109-0.248), liraglutide (ROR: 0.161; 95% CI: 0.091-0.284), empagliflozin (ROR: 0.234; 95% CI: 0.146-0.377), and metformin (ROR: 0.387; 95% CI: 0.340-0.440). No inverse associations were found for other weight loss-inducing drugs such as phentermine, bupropion, topiramate, zonisamide, and amphetamine. An exception was naltrexone (ROR: 0.556; 95% CI: 0.384-0.806). Conclusion: Our findings suggest a potential consideration for repurposing anti-diabetic weight loss-inducing drugs including semaglutide, dulaglutide, and liraglutide (glucagon-like peptide-1 receptor agonists), empagliflozin (sodium-glucose cotransporter-2 inhibitor), and metformin (biguanide), for MS. This warrants validation through rigorous methodologies and prospective studies.

Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis.

Importance: Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. Objective: To identify CSF biological measures associated with progressive MS pathobiology. Design, Setting, and Participants: This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). Exposures: Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. Main Outcomes and Measures: Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). Results: The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = -0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = -0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). Conclusions and Relevance: In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

Diffusion basis spectrum imaging and diffusion tensor imaging predict persistent black hole formation in multiple sclerosis.

BACKGROUND AND OBJECTIVES: Diffusion basis spectrum imaging (DBSI) extracts multiple anisotropic and isotropic diffusion tensors, providing greater histopathologic specificity than diffusion tensor imaging (DTI). Persistent black holes (PBH) represent areas of severe tissue damage in multiple sclerosis (MS), and a high PBH burden is associated with worse MS disability. This study evaluated the ability of DBSI and DTI to predict which acute contrast-enhancing lesions (CELs) would persist as T1 hypointensities (i.e. PBHs) 12 months later. We expected that a higher radial diffusivity (RD), representing demyelination, and higher DBSI-derived isotropic non-restricted fraction, representing edema and increased extracellular space, of the acute CEL would increase the likelihood of future PBH development. METHODS: In this prospective cohort study, relapsing MS patients with ≥1 CEL(s) underwent monthly MRI scans for 4 to 6 months until gadolinium resolution. DBSI and DTI metrics were quantified when the CEL was most conspicuous during the monthly scans. To determine whether the CEL became a PBH, a follow-up MRI was performed at least 12 months after the final monthly scan. RESULTS: The cohort included 20 MS participants (median age 33 years; 13 women) with 164 CELs. Of these, 59 (36 %) CELs evolved into PBHs. At Gd-max, DTI RD and AD of all CELs increased, and both metrics were significantly elevated for CELs which became PBHs, as compared to non-black holes (NBHs). DTI RD above 0.74 conferred an odds ratio (OR) of 7.76 (CI 3.77-15.98) for a CEL becoming a PBH (AUC 0.80, CI 0.73-0.87); DTI axial diffusivity (AD) above 1.22 conferred an OR of 7.32 (CI 3.38-15.86) for becoming a PBH (AUC 0.75, CI 0.66-0.83). DBSI RD and AD did not predict PBH development in a multivariable model. At Gd-max, DBSI restricted fraction decreased and DBSI non-restricted fraction increased in all CELs, and both metrics were significantly different for CELs which became PBHs, as compared to NBHs. A CEL with a DBSI non-restricted fraction above 0.45 had an OR of 4.77 (CI 2.35-9.66) for becoming a PBH (AUC 0.74, CI 0.66-0.81); a CEL with a DBSI restricted fraction below 0.07 had an OR of 9.58 (CI 4.59-20.02) for becoming a PBH (AUC 0.80, 0.72-0.87). CONCLUSION: Our findings suggest that greater degree of edema/extracellular space in a CEL is a predictor of tissue destruction, as evidenced by PBH evolution.

Development of an LC-MS/MS Method to Measure Sphingolipids in CSF from Patients with Multiple Sclerosis.

Multiple sclerosis is an inflammatory and degenerative disease characterized by different clinical courses including relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). A hallmark of patients with multiple sclerosis (pwMS) includes a putative autoimmune response, which results in demyelination and neuroaxonal damage in the central nervous system. Sphingolipids in cerebrospinal fluid (CSF) have been proposed as potential biomarkers reflective of disease activity in pwMS. Hence, sensitive methods to accurately quantify sphingolipids in CSF are needed. In this study, we report the development of a sensitive high-throughput multiplexed liquid chromatography coupled to a tandem mass spectrometry method to perform quantitation on 14 species of sphingolipids in human CSF. We applied this method to measure CSF sphingolipids in healthy controls (n = 10), PPMS (n = 27), and RMS (n = 17) patients before and after ocrelizumab treatment. The median CSF levels of the 14 sphingolipids measured herein was higher in PPMS (17.2 ng/mL) and RMS (17.6 ng/mL) when compared with the healthy controls (13.8 ng/mL). Levels of sphingolipids were decreased by 8.6% at week 52 after treatment with ocrelizumab in RMS patients but not in PPMS patients. Specifically, C16 glucosylceramide (-26%; P = 0.004) and C18 ceramides (-13%; P = 0.042) decreased from baseline in RMS patients. Additionally, in PPMS patients C16 glucosylceramide levels correlated with CSF neurofilament heavy levels at baseline (Rho =0.532; P = 0.004) and after treatment (Rho =0.424; P = 0.028). Collectively, these results indicate that CSF sphingolipid levels are altered in pwMS and treatment with ocrelizumab results in significant shifts in the sphingolipid profile that may reflect a reduction in disease activity supporting further investigation into sphingolipids as tools to monitor disease state. SIGNIFICANCE STATEMENT: This study describes the development of a new method to measure 14 sphingolipid species in CSF. These results demonstrate that sphingolipids levels are elevated in CSF from pwMS compared to healthy controls. Distinct sphingolipid signatures were observed between patients with different clinical disease courses, and these lipid signatures changed after treatment with ocrelizumab, especially in RMS patients. This method enables further investigation into the role of sphingolipids as candidate biomarkers in pwMS and other central nervous system disorders.

Quantitative Analysis of S1PR1 Expression in the Postmortem Multiple Sclerosis Central Nervous System.

Multiple sclerosis (MS) is an immune-mediated disease that is characterized by demyelination and inflammation in the central nervous system (CNS). Previous studies demonstrated that sphingosine-1-phosphate receptor (S1PR) modulators effectively inhibit S1PR1 in immune cell trafficking and reduce entry of pathogenic cells into the CNS. Studies have also implicated a nonimmune, inflammatory role of S1PR1 within the CNS in MS. In this study, we explored the expression of S1PR1 in the development and progression of demyelinating pathology of MS by quantitative assessment of S1PR1 expression using our S1PR1-specific radioligand, [3H]CS1P1, in the postmortem human CNS tissues including cortex, cerebellum, and spinal cord of MS cases and age- and sex-matched healthy cases. Immunohistochemistry with whole slide scanning for S1PR1 and various myelin proteins was also performed. Autoradiographic analysis using [3H]CS1P1 showed that the expression of S1PR1 was statistically significantly elevated in lesions compared to nonlesion regions in the MS cases, as well as normal healthy controls. The uptake of [3H]CS1P1 in the gray matter and nonlesion white matter did not significantly differ between healthy and MS CNS tissues. Saturation autoradiography analysis showed an increased binding affinity (Kd) of [3H]CS1P1 to S1PR1 in both gray matter and white matter of MS brains compared to healthy brains. Our blocking study using NIBR-0213, a S1PR1 antagonist, indicated [3H]CS1P1 is highly specific to S1PR1. Our findings demonstrated the activation of S1PR1 and an increased uptake of [3H]CS1P1 in the lesions of MS CNS. In summary, our quantitative autoradiography analysis using [3H]CS1P1 on human postmortem tissues shows the feasibility of novel imaging strategies for MS by targeting S1PR1.

Humoral immune response to COVID-19 mRNA vaccines in patients with relapsing multiple sclerosis treated with ofatumumab.

BACKGROUND: There are limited data available regarding the impact of ofatumumab, an anti-CD20 B-cell-depleting monoclonal antibody for relapsing multiple sclerosis (RMS), on vaccination response. The study objective was to assess humoral immune response (HIR) to non-live coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination in patients with RMS treated with ofatumumab. METHODS: This was an open-label, single-arm, multicenter, prospective pilot study of patients with RMS aged 18-55 years who received 2 or 3 doses of a COVID-19 mRNA vaccine after ≥1 month of subcutaneous ofatumumab (20 mg/month) treatment. The primary endpoint was the proportion of patients achieving HIR, as defined by local laboratory severe acute respiratory syndrome coronavirus-2 qualitative immunoglobulin G assays. Assay No. 1 was ≥14 days after the second or third vaccine dose. Assay No. 2 was 90 days thereafter. RESULTS: Of the 26 patients enrolled (median [range] age: 42 [27-54] years; median [range] ofatumumab treatment duration: 237 [50-364] days), HIR was achieved by 53.9% (14/26; 95% CI: 33.4 - 73.4%) at Assay No. 1 and 50.0% (13/26; 95% CI: 29.9 - 70.1%) at Assay No. 2. Patients who received 3 vaccine doses had higher HIR rates (Assay No. 1: 70.0% [7/10]; Assay No. 2: 77.8% [7/9]) than those who received 2 doses (Assay No. 1: 46.7% [7/15]; Assay No. 2: 42.9% [6/14]). Of patients aged <40 years without previous anti-CD20 therapy, HIR was achieved by 90.0% (9/10) at Assay No. 1 and 75.0% (6/8) at Assay No. 2. No serious adverse events were reported. CONCLUSION: Patients with RMS treated with ofatumumab can mount HIRs following COVID-19 vaccination. A plain language summary, infographic and a short video summarizing the key results are provided in supplementary material. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT04847596 (https://clinicaltrials.gov/ct2/show/NCT04847596).

Antibody response to SARS-CoV-2 vaccines in patients with relapsing multiple sclerosis treated with evobrutinib: A Bruton's tyrosine kinase inhibitor.

BACKGROUND: Evobrutinib is an oral, central nervous system (CNS)-penetrant and highly selective covalent Bruton's tyrosine kinase inhibitor under clinical development for patients with relapsing multiple sclerosis (RMS). OBJECTIVE: To investigate the effect of evobrutinib on immune responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinated patients with RMS from a Phase II trial (NCT02975349). METHODS: A post hoc analysis of patients with RMS who received evobrutinib 75 mg twice daily and SARS-CoV-2 vaccines during the open-label extension (n = 45) was conducted. Immunoglobulin (Ig)G anti-S1/S2-specific SARS-CoV-2 antibodies were measured using an indirect chemiluminescence immunoassay. RESULTS: In the vaccinated subgroup, mean/minimum evobrutinib exposure pre-vaccination was 105.2/88.7 weeks. In total, 43 of 45 patients developed/increased S1/S2 IgG antibody levels post-vaccination; one patient's antibody response remained negative post-vaccination and the other had antibody levels above the upper limit of detection, both pre- and post-vaccination. Most patients (n = 36/45), regardless of pre-vaccination serostatus, had a 10-100-fold increase of antibody levels pre- to post-vaccination. Antibody levels post-booster were higher versus post-vaccination. CONCLUSION: These results suggest evobrutinib, an investigational drug with therapeutic potential for patients with RMS, acts as an immunomodulator, that is, it inhibits aberrant immune cell responses in patients with RMS, while responsiveness to foreign de novo and recall antigens is maintained.

Blood neurofilament light levels predict non-relapsing progression following anti-CD20 therapy in relapsing and primary progressive multiple sclerosis: findings from the ocrelizumab randomised, double-blind phase 3 clinical trials.

BACKGROUND: Neurofilament light chain (NfL), a neuronal cytoskeletal protein that is released upon neuroaxonal injury, is associated with multiple sclerosis (MS) relapsing activity and has demonstrated some prognostic ability for future relapse-related disease progression, yet its value in assessing non-relapsing disease progression remains unclear. METHODS: We examined baseline and longitudinal blood NfL levels in 1421 persons with relapsing MS (RMS) and 596 persons with primary progressive MS (PPMS) from the pivotal ocrelizumab MS trials. NfL treatment-response and risk for disease worsening (including disability progression into the open-label extension period and slowly expanding lesions [SELs] on brain MRI) at baseline and following treatment with ocrelizumab were evaluated using time-to-event analysis and linear regression models. FINDINGS: In persons from the RMS control arms without acute disease activity and in the entire PPMS control arm, higher baseline NfL was prognostic for greater whole brain and thalamic atrophy, greater volume expansion of SELs, and clinical progression. Ocrelizumab reduced NfL levels vs. controls in persons with RMS and those with PPMS, and abrogated the prognostic value of baseline NfL on disability progression. Following effective suppression of relapse activity by ocrelizumab, NfL levels at weeks 24 and 48 were significantly associated with long-term risk for disability progression, including up to 9 years of observation in RMS and PPMS. INTERPRETATION: Highly elevated NfL from acute MS disease activity may mask a more subtle NfL abnormality that reflects underlying non-relapsing progressive biology. Ocrelizumab significantly reduced NfL levels, consistent with its effects on acute disease activity and disability progression. Persistently elevated NfL levels, observed in a subgroup of persons under ocrelizumab treatment, demonstrate potential clinical utility as a predictive biomarker of increased risk for clinical progression. Suppression of relapsing biology with high-efficacy immunotherapy provides a window into the relationship between NfL levels and future non-relapsing progression. FUNDING: F. Hoffmann-La Roche Ltd.

Targeting miR-223 enhances myeloid-derived suppressor cell suppressive activities in multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is an incurable autoimmune inflammatory demyelinating disease of the central nervous system. Several MS medications can modify disease course through effects on adaptive immune cells, while drugs targeting innate immunity are under investigation. Myeloid-derived suppressor cells (MDSCs) which arise during chronic inflammation, are defined by their T-cell immunosuppressive functions. MiR-223 modulates myeloid cell maturation and expansion, including MDSCs. METHODS: MDSCs isolated from healthy controls (HC) and people with MS (pwMS) were co-cultured with CD4+ T-cells to study their immunosuppressive activities in vitro. Cytokines and chemokines concentration were evaluated by Luminex assay in the serum of HC, pwMS, and other neuroinflammatory diseases and correlated with MDSC activities. RESULTS: MDSC suppressive functions are dysregulated in pwMS compared to HC, which was reversed by glucocorticoids (GC). GC specifically downregulated miR-223 levels in MDSCs and increased the expression of STAT3. In vitro assay showed that miR-223 inhibition enhanced MDSC suppressive activity, STAT3 dependently. By multiple linear regression analysis, we demonstrated that MDSC phosphorylated STAT3 was correlated with serum GM-CSF in HC and pwMS. CONCLUSIONS: These results suggest that miR-223 could be a therapeutic target for enhancing MDSC's suppressive activities as an alternative to GC.

Demographics and baseline disease characteristics of Black and Hispanic patients with multiple sclerosis in the open-label, single-arm, multicenter, phase IV CHIMES trial.

BACKGROUND: Black/African American patients with multiple sclerosis (BpwMS) and Hispanic/Latino patients with multiple sclerosis (HpwMS), who historically have been underrepresented in multiple sclerosis (MS) clinical trials, exhibit greater disease severity and more rapid disease progression than White patients with MS (WpwMS). The lack of diversity and inclusion in clinical trials, which may be due to barriers at the system, patient and study levels, impacts the ability to effectively assess risks, benefits and treatment responses in a generalized patient population. METHODS: CHIMES (Characterization of Ocrelizumab in Minorities With Multiple Sclerosis), an open-label, single-arm, multicenter, phase IV study of self-identified BpwMS and HpwMS aged 18-65 years with relapsing MS and an Expanded Disability Status Score (EDSS) of ≤5.5, was developed in collaboration with patients with MS, national advocacy groups and clinical researchers. Patients were enrolled at study centers across the US, including Puerto Rico, and 1 site in Kenya. RESULTS: A total of 182 patients enrolled in CHIMES: 113 (62.1%) were BpwMS, and 69 (37.9%) were HpwMS; the mean (SD) baseline EDSS score was 2.4 (1.4), and 62.6% of patients were treatment naive. Using the pooled non-BpwMS/HpwMS group in the OPERA ocrelizumab trials as a reference population, patients enrolled in CHIMES were younger, had a higher mean body mass and had a greater T2 lesion volume but similar T2 lesion number on MRI. CONCLUSION: BpwMS and HpwMS have been consistently underrepresented in clinical trials, limiting the understanding of disease biology and response to treatment in this population. Data from the CHIMES study revealed differences in demographics and some baseline disease characteristics and disease burden between BpwMS and HpwMS vs WpwMS. These differences could have an impact when assessing clinical outcomes in BpwMS and HpwMS. GOV IDENTIFIER: NCT04377555.

Obesity, gut microbiota, and multiple sclerosis: Unraveling the connection.

Obesity is associated with chronic mild-grade systemic inflammation and neuroinflammation. Obesity in early childhood and adolescence is also a significant risk factor for multiple sclerosis (MS) development. However, the underlying mechanisms that explain the link between obesity and MS development are not fully explored. An increasing number of studies call attention to the importance of gut microbiota as a leading environmental risk factor mediating inflammatory central nervous system demyelination, particularly in MS. Obesity and high-calorie diet are also associated with disturbances in gut microbiota. Therefore, gut microbiota alteration is a plausible connection between obesity and the increased risk of MS development. A greater understanding of this connection could provide additional therapeutic opportunities, like dietary interventions, microbiota-derived products, and exogenous antibiotics and probiotics. This review summarizes the current evidence regarding the relationships between MS, obesity, and gut microbiota. We discuss gut microbiota as a potential link between obesity and increased risk for MS. Additional experimental studies and controlled clinical trials targeting gut microbiota are warranted to unravel the possible causal relationship between obesity and increased risk of MS.